Leading Article

Ind. J. Tub., 1994, 41, 131

HEPATIC TUBERCULOSIS
Tuberculosis was declining in the West but has shown a reverse trend after the appearance of the AIDS epidemic, making tuberculosis a global health problem once again. Liver involvement in tuberculosis, though common both in pulmonary and extra-pulmonary tuberculosis, is usually clinically silent1. Occasionally, local signs and symptoms may be prominent in hepatic tuberculosis, and may constitute the initial or sole presenting feature of the disease. However, even in developing countries, liver tuberculosis accompanied by local symptoms is an uncommon entity. A study from South Africa showed that liver tuberculosis accounted for only 1.2% of all cases of tuberculosis diagnosed at a general hospital2. Lack of familiarity with this condition was apparently responsible for the diagnosis of hepatic tuberculosis being made at autopsy or surgery3 in the past. Since tuberculosis remains a potentially curable disease, an awareness of its protean manifestations is very essential. Tubercle bacilli reach the liver by way of hematogenous dissemination : the portal of entry in the case of miliary tuberculosis is through the hepatic artery whereas in the case of focal liver tuberculosis it is via the portal vein. Irrespective of the mode of entry, the liver responds by granuloma formation. Tuberculous granulomata are most frequently found in the periportal areas (zone 1 of Rappaport) but may occasionally occur in zone 31. Both caseating and non-caseating granulomas are seen. In focal tuberculosis, various granulomas may coalesce to form a large tumor like tuberculoma. A tuberculoma which has undergone extensive caseating and liquefaction necrosis forms a tubercular abscess. The nomenclature of hepatic tuberculosis is confusing. Multiple terms like tubercular hepatitis2, local tuberculosis3,4, secondary tuberculosis4, isolated tuberculosis5, and atypical tuberculosis6, have been used by various authors and the same term may have a different connotation when used by different authors. Thus, local tuberculosis of the liver may either mean a lesion > 2 mm diameter on gross examination4 or a selective involvement of the liver without clinically apparent disease of other organs3. There is, therefore, a dire need for a uniformly acceptable classification and nomenclature. Broadly speaking, hepatic tuberculosis presents in three forms7. The most common form is the diffuse hepatic involvement, seen along with pulmonary or miliary tuberculosis, in 50% to 80% of patients dying of pulmonary tuberculosis. Despite the diffuse involvement of the liver pathologically, symptoms of liver disease are absent. The second form is a diffuse hepatic infiltration without recognizable pulmonary involvement (granulomatous hepatitis). The third much rarer form presents as a focal/local tuberculoma or abscess.
Granulomatous Liver Disease

This form was referred to as granulomatous hepatitis or tubercular hepatitis in the older literature2. These terms, though technically incorrect, have the merit of distinguishing the frequent asymptomatic seeding of the liver in miliary tuberculosis from the syndrome with fever and other constitutional symptoms but without pulmonary lesions, the common denominator in both forms being the presence of diffuse hepatic granulomas. Hepatic granulomas have varied aetiology and show considerable geographic variation. While the occurrence of sarcoidosis, primary biliary cirrhosis and fungal disease is high in the Western hemisphere1, tuberculosis is the commonest cause in India8. Therefore, the finding of liver granulomas histologically, even in the absence of caseation, necrosis/AFB, is accepted as evidence of tubercular aetiology in most parts of Asia and Africa unless proven otherwite8,9. Fever is the commonest symptom (63% - 99%) in tubercular hepatic granulomatosis followed by weight loss (50%-84%) and abdominal pain (46%-70%)2,4,8,10. Hepatomegaly is present in more than half the patients whereas splenomegaly is present in one third2,8,10. Needle biopsy is an excellent method for making the diagnosis; none of the imaging modalities (ultrasound, CT and MRI) is useful because of the small size (2mm) of the granulomas.

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Local Hepatic Tuberculosis

Local hepatic tuberculosis, defined as tubercles > 2 mm in diameter, usually occurs along with a tuberculous focus elsewhere11. Isolated hepatic tuberculoma (syn. nodular hepatic tuberculosis, macronodular hepatic tuberculosis) is1 perhaps the rarest form of local hepatic tuberculosis since less than 25 cases had been reported in world literature till 19903. Local hepatic tuberculosis has mostly been reported from South Africa and the Philippines4,9. In the former study4, local hepatic tuberculosis accounted for 14% of the 143 cases of hepatic tuberculosis in adults, (the rest had miliary involvement) Constitutional symptoms in the form of fever, anorexia and weight loss were present in 55%-90% of the patients. Abdominal pain is present in 65%-87% of patients3,4, but jaundice is uncommon, being present in 20%-35% of patients3,4,9. Most authors agree that jaundice with bilirubin values between 2.3 mg% and 5.8 mg% is due either to porta hepatis nodes causing biliary compression or to pericholangitis or the rupture of a tuberculous granuloma into the bile ducts. Hepatomegaly and splenomegaly are the commonest findings, being present in 70%96%3,4,9 and 25%-55%4,9 of patients respectively. Liver is hard and nodular in about half the cases9,12. Findings from liver function tests are non-specific with the notable exception of an elevated alkaline phosphatase level in 50%-87%3,4 of patients. Seventy five percent of patients with local tuberculosis of liver have abnormal chest roentgenograms2 compared with only two of 21 patients with isolated hepatic tuberculosis3. Calcification in the hepatic region on plain X-ray of the abdomen may occasionally be seen in local hepatic tuberculosis9. Imaging techniques (radionuclide scan, ultrasonography, CT and MRI scans) are useful in making the diagnosis of tuberculoma or tubercular abscess. On CT scan, liver tuberculoma appears as an unenhancing, central, low density lesion due to caseation necrosis with a slightly enhancing peripheral rim corresponding to surrounding granulation tissue13. These findings though suggestive of tuberculosis have also been seen in necrotic tumours, such as metastatic carcinoma and hepatocellular carcinoma. Preliminary reports on MRI findings in large tuberculomas suggest that MRI findings are non-specific14. Ultrasonically, a tuberculoma

may be seen as a hypoechoic lesion without a distinct wall resulting from the conglomeration of numerous small tubercles or as a low density lesion with a hyperechoic rim relating to a tuberculous abscess. In both the cases, calcification may be observed15. AIDS and Hepatic Tuberculosis : The outbreak of the AIDS epidemic in 1981 has been responsible for the global resurgence of tuberculosis16. Nearly 10% of patients with AIDS in the West are found infected with Mycobacterium tuberculosis17 and more than 50% of patients with AIDS and tuberculosis have the extrapulmonary forms of tuberculosis18,19. While involvement of liver with Mycobacterium avium intracellulare (MAI) in AIDS patients is well recognized, and even constitutes a diagnostic criterion, the hepatic involvement with Mycobacterium tuberculosis is much less common, and has been recognized only recently1923 . In 1987, the presence of extrapulmonary tuberculosis along with HIV seropositivity was included as case definition of AIDS by the Centres for Disease Control (CDC)24. Fever and abdominal pain are the commonest presenting features of hepatic tuberculosis in AIDS due to the frequent occurrence of tubercular liver abscesses in such patients21,23. Aspirates from such abscess show an abundance of AFB. Unlike involvement with MAI for which no drug combination is effective therapy - the standard antituberculosis regimensis highly efficacious in M. Tuberculosis innfection21,223.
Diagnosis

As is true for tuberculous involvement of other organs, the final diagnosis of hepatic tuberculosis rests on histopathologic evidence of caseating granuloma or demonstration of AFB on smear or culture of biopsy specimen. This holds true both for local as well as diffuse hepatic tuberculous involvement of the liver. Using needle biopsy specimen, epithelioid granuloma formation can be demonstrated in liver tuberculosis in 80% -100% of cases; caseation necrosis in 30% - 83% and AFB on smear examination in 0% - 59% of cases2,4,8,24. Non-specific features like fatty change, Kuppfer cell hyperplasia, focal parenchymal necrosis and inflammatory cell infiltration may exist pan passu with specific tuberculosis lesions

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in a high proportion of patients . The wide variation in these positive findings from different series may be related to the type of hepatic involvement i.e. the local or diffuse form, quantum of liver tissue in biopsy material and the effort of the pathologist. AFB positivity was significantly higher in autopsy material (83%) visa-vis needle biopsy specimens (20%), even in the same study, giving an overall confirmation rate of 33%4. Demonstration of AFB is more common in 'tubercular abscess verses solid tuberculomas because AFB are abundant in liquefied caseous material. For unknown reasons, the results of AFB demonstration in liver tissue in studies reported from India and the Philippines have been dismal: AFB were not found in three series from India, despite the presence of caseation necrosis and epithelioid granulomas5,8,25. In the Philippines study, AFB could be demonstrated in 2 of 30 cases of hepatic tuberculosis at autopsy9. A problem in the tissue diagnosis of local hepatic tuberculosis is the high rate of false negative results with needle bioposy technique. Guided percutaneous liver biopsy was successful in only two of 21 cases of local hepatic tuberculosis3. Even at laparotomy, the correct diagnosis may be missed3. Laparoscopy combined with direct vision liver biopsy was successful in the diagnosis of liver tuberculoma in all the cases, as reported from the Philippines9 and may be the preferred mode of investigation for this form of the disease. Treatment and Prognosis: Hepatic tuberculosis is treated like any other extrapulmonary tuberculosis lesion. Chemotherapy with standard anti-tuberculosis drugs remains the corner stone of treatment. This is true for both diffuse as well as the local forms of the disease. Most authors have used four drugs (INH, Rifampicin, Streptomycin and Pyrazinamide) during the initial two months, followed by INH and Rifampicin for the next seven months8,10. There are no reports on short course chemotherapy for hepatic tuberculosis. The above given recommendations have been endorsed by the CDC for the management of tuberculosis in patients with HIV infection25. Cumulative mortality for hepatic tuberculosis ranges between 15% and 42%2,9. The factors associated with adverse prognosis are: age < 20

8,24

years, miliary tuberculosis, concurrent steroid therapy, AIDS, cachexia, associated cirrhosis and liver failure. The importance of associated disease in the outcome of hepatic tuberculosis cannot be overstressed : nearly 50% of the deaths in the Philippines study were due to respiratory failure and another third from ruptured esophageal varices due to associated cirrhosis.9 Even in patients with AIDS and tuberculosis, the cause of death is invariably the former17. Drug induced hepatotoxicity is not mentioned in most reports of liver tuberculosis even with the widespread use of Rifampicin2,10. In all probability, this may be due to the small number of patients with hepatic tuberculosis rather than a true absence of hepatotoxicity in such cases. This suggests the relative safety of the use of even four drug regimens in hepatic tuberculosis with the overall risk of drug induced liver disease being the same as that associated with the treatment of pulmonary tuberculosis. Essop et al2 have shown that when INH and Rifampicin are used together, mortality rates are significantly lower than those with the use of non-Rifampicin containing regimes (0% vs 17% - 50%). In addition to chemotherapy, anecdotal reports of successful percutaneous drainage of tuberculous liver abscesses have been made.26 In summary, symptomatic hepatic tuberculosis is uncommon. The number of cases of hepatic tuberculosis is expected to rise on account of the AIDS epidemic. Since clinical features are protean and mimic neoplajtic and infective hepatic disorders, the diagnosis requires a high index of suspicion. The presence of hepatomegaly with or without right upper quadrant pain in a patient with PUO should merit consideration of hepatic tuberculosis. The demonstration of granulomas on liver biopsy remains the most sensitive diagnostic procedure, As for other forms of extra pulmonary tuberculosis, hepatic tuberculosis is a potentially curable disease. Good results have been obtained with four drug regimens without any added risk of hepatotoxicity in both immunosuppressed and immunocompetent patients.

Department of Gastroenterology G.B. Pant Hospital, New Delhi-110 002.

A.S. Purl, A.K. Nayyar and J.C. Vij

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PURI ET AL 15. Brauner, M., Buffard, M.D., Jeantils, V. et al. Sonography and computed tomography of macroscopic tuberculosis of the liver. J. Clin. Ultrasound; 1989,17,563. Rieder, H.L., Cauthen G.M., Bloch,, A.B. et al. Tuberculosis and acquired immunodeficiency syndrome. Arch. Intern. Med.; 1989,149,1268. Fauci, A.S., Lane, H.C. The acquired immunodeficiency syndrome. In Wilson J.D. et al. (eds) Harrison's principles of internal medicine, 12th ed. McGraw Hill, New York; 1991, p. 1402. Sundaram, G., McDonald, R.J., Maniatis, T. et al. Tuberculosis as a manifestation of the acquired immunodeficiency syndrome. J.A.M.A.; 1986,256, 362. Soriano, V, Tor, J., Domenecn, E., et al. Abdominal tuberculosis in patients with acquired immunodeficiency syndrome. Med. Clin. (Barcelona); 1991, 97.121. Rosengart, T.K., Coppa G.F. Abdominal mycobacterium infections in immunocomprised patients. Am. J. Surg.; 1990,159,125. Pottipati, A.R., Dave, P.B., Gumaste, V., Vieux, U. Tuberculous abscess of the liver in acquired immunodeficiency syndrome. J. Clin. Gasjroenterol; 1991,13,549. Kielhofner, M.A., Hamill, R.J. Focal hepatic tuberculosis in a patient with acquired immunodeficiency syndrome. South Med. J.; 1991,84,401. Weinberg, J.J., Cohen, P., Malhotra, R. Primary tuberculous abscess associated with the human immunodeficiency virus. Tubercle; 1988, 69, 145 Khosla, S.N., Chhabra, U.K., Mehrotra, G.C. Liver in abdominal tuberculosis. J. Assoc. Physician India; 1986,34,501. Centres for Disease Control. Diagnosis and management of mycobactcrial infection and disease in persons with human immunodeficiency virus infection. Ann. Intern. Med. 1987,106,254. Mustard, R.A., Mackenzie, R.L., Gray, R.G. Percutaneous drainage of a liver abscess. Can. J. Surg.; 1986,29,449.

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1. Reynolds, T.B., Campra, J.L., Peters, R.L., Hepatic granulomata. In Zakim D, Boyer T.D. (eds.) Hepatology - A textbook of liver disease, 2nd ed. W.B. Saunders, Philadelphia; 1990, p. 1098. Essop, A.R., Posen, J.A., Hodkinson, J.H., Segal I. Tuberculosis hepatitis : A clinical review of 96 cases. Quart. J. Med.; 1984, S3,465. Oliva, A. Duarte, B., Jonasson, O., Nadimpalli, V. The nodular form of local hepatic tuberculosis. J. Clin. Gastroenterol; 1990, 12, 166. Hersch, C. Tuberculosis of the liver. South Afr. Med. J.; 1964, 38, 857. Johri, B.S., Kane, M.P., Mudbhatkal, N.S. Isolated tuberculosis of the liver. Indian J. Med. Sci.; 1970, 24, 16. Cleve E. Atypical tuberculosis of the liver with jaundice. Ann. Intern. Med.; 1954, 41, 251. Spiegel, C.T., Tuczon, C.U. Tuberculosis liver abscess. Tubercle; 1984, 65,127. Plumber, S.T., Pipalia, D.H., Vora, I.M., Bhambhure, N., Naik, S.R. Hepatic granulomas: Profile and follow up of 10 cases responding to antituberculous therapy. J. Assoc. Physician India; 1987, 35, 207. Alvarez, S.Z., Carpio, R. Hepatobiliary tuberculosis. Dig. Dis. Sci.; 1983,28,193. Maharaj, B., Leary, W.P., Pudifin, D.J. A prospective study of hepatic tuberculosis in 41 black patients. Quart. J. Med.; 1987,63,517. Leader, S.A. Tuberculosis of the liver and gall bladder with abscess formation : A review and case report. Ann. Intern. Med.; 1952,37,594. Terry R.B., Gunnar R.M. Primary miliary tuberculosis of the liver, J.A.M.A.; 1957,164, 150. Kawamori, Y., Matsui, O., Kitagawa, K. et al. Macronodular tuberculoma of the liver : CT and MR findings. A.J.R.; 1992,158, 311. Blangy, S., Cornud, F., Sibert, A. Hepatic tuberculosis presenting as tumoral disease. Gastrointest Radiol.; 1988,13,52.

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